Molecular mechanisms of fatty liver disease: role of the protein DBC1

脂肪肝疾病的分子机制：蛋白质 DBC1 的作用

• 批准号: 8288739
• 负责人: Eduardo N Chini
• 金额: $ 25.92万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288739
• 关键词: Accounting; Address; Age; American; Animal Model; Binding; Biochemical; Caloric Restriction; Cardiovascular system; Cell model; Cessation of life; Data; Deacetylase; Developed Countries; Developing Countries; Development; Diet; Disease; Dissociation; Enzymes; Fatty Liver; Fatty acid glycerol esters; Future; Genes; Health; Hepatic; Investigation; KIAA1967 gene; Knock-out; Knockout Mice; Laboratories; Lead; Light; Liver; Liver diseases; Longevity; Malignant Neoplasms; Mediating; Metabolic; Metabolic syndrome; Metabolism; Molecular; Molecular Biology Techniques; Mus; Organism; Pathway interactions; Patients; Physiological; Play; Process; Proteins; Public Health; Regulation; Reporting; Resistance; Role; Starvation; Testing; Therapeutic; Wild Animals; adenylate kinase; base; fatty acid oxidation; in vitro Assay; in vivo; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; meetings; member; mortality; non-alcoholic fatty liver; novel; oxidation; trend

DESCRIPTION (provided by applicant): Recently the American Association for the Study of Liver Disease stated that "...Overall, patients with non-alcoholic fatty liver disease (NAFLD) have reduced long-term survival, with liver disease accounting for about 10% of overall mortality.... Clearly it appears that NAFLD will become a more prevalent problem in coming years..." This indicates that NAFLD will become a major public health issue in the near future. However, to date, therapeutic options for this disease are limited. In this regard, it is imperative to further understand the molecular mechanisms that modulate the development of liver steatosis. We observed that the protein Deleted in Breast Cancer 1 (DBC1) plays a crucial role in the development of experimental liver steatosis. In particular we found that mice knocked out for DBC1 are resistant to high fat diet-induced liver steatosis, while the systemic metabolic syndrome was not ameliorated. This suggests that DBC1 controls intrinsic hepatic mechanisms involved in the development of liver steatosis. To date very little is known about the physiological and biochemical roles of DBC1, however recent studies indicate that DBC1 binds and inhibits the enzyme SIRT1. SIRT1 is a NAD-dependent deacetylase that controls metabolism, ageing and longevity. In fact, it has been proposed that SIRT1 is a metabolic master switch. Pharmacological activation of SIRT1 protects against liver steatosis, at least in part, via stimulation of the AMP kinase (AMPK) that subsequently decreases lipogenesis and increases fatty acid oxidation. Although the metabolic actions of SIRT1 are the subject of intense investigation; much less is known about regulation of SIRT1. In fact, the mechanisms that modulate SIRT1 expression and activity remain elusive. In this regard, the characterization of DBC1 as an endogenous inhibitor of SIRT1, and the determination of the mechanisms that regulate the DBC1-SIRT1 interaction are of extreme importance. It is possible that modulation of DBC1-SIRT1 interaction plays a key role in the regulation of SIRT1 function during different metabolic conditions, including diet-induced steatosis. An increase in interaction between DBC1 and SIRT1 may also provide the molecular basis for the decrease in SIRT1 activity reported in animal models of diet-induced liver steatosis. Thus, our Central Hypothesis is that DBC1 plays a crucial role in the development of liver steatosis by direct binding and inhibiting SIRT1, with the subsequent modulation of downstream effects of SIRT1 on hepatic lipogenesis and 2-oxidation via AMPK. To test this hypothesis, the following specific aims will be addressed: Aim 1. Study the role of SIRT1 in DBC1-mediated regulation of liver steatosis. Aim 2. Characterize the role of DBC1 in the regulation of SIRT1 activity during different caloric loads and determine the molecular mechanisms that regulate the DBC1-SIRT1 interaction. Aim 3. Determine the biochemical mechanisms, downstream from SIRT1, by which DBC1 regulates the development of liver steatosis: role of AMPK. Collectively, these studies will lead to an in depth and extremely novel understanding of the physiological roles of DBC1 as a regulator of SIRT1, liver fat metabolism and hepatic steatosis. PUBLIC HEALTH RELEVANCE: Non alcoholic fatty liver disease (NAFLD) is a major health problem worldwide. As recently stated by members of the future trend meeting of the American Association for the Study of Liver Disease, "...Overall, patients with NAFLD have reduced long-term survival, with liver disease accounting for about 10% of overall mortality, surpassed only by malignancy and cardiovascular deaths. Clearly it appears that NAFLD will become a more prevalent problem in coming years..." ). These alarming data and predictions clearly show that it is imperative to further understand the molecular mechanisms that modulate the development of liver steatosis.

描述（由申请人提供）：最近美国肝病研究协会说：“……总体而言，非酒精性脂肪肝病（NAFLD）的患者降低了长期生存，肝病约为总体死亡率的约10％。...显然，NAFLD似乎在未来几年内变得更加普遍……但是，迄今为止，这种疾病的治疗选择有限。在这方面，必须进一步了解调节肝脏脂肪变性发展的分子机制。我们观察到，在乳腺癌1（DBC1）中删除的蛋白质在实验性肝脏脂肪变性的发展中起着至关重要的作用。特别是我们发现，撞倒DBC1的小鼠对高脂饮食诱导的肝脏脂肪变性具有抗性，而全身代谢综合征没有得到改善。这表明DBC1控制着肝脏脂肪变性发展的内在肝机制。迄今为止，关于DBC1的生理和生化作用知之甚少，但是最近的研究表明，DBC1结合并抑制酶SIRT1。 SIRT1是一种依赖NAD的脱乙酰基酶，控制代谢，衰老和寿命。实际上，已经提出SIRT1是一种代谢主开关。 SIRT1的药理激活至少部分通过刺激AMP激酶（AMPK）来预防肝脏脂肪变性，随后降低脂肪生成并增加脂肪酸氧化。尽管SIRT1的代谢作用是进行激烈调查的主题；关于SIRT1的调节，知之甚少。实际上，调节SIRT1表达和活性的机制仍然难以捉摸。在这方面，将DBC1作为SIRT1的内源性抑制剂的表征，并且确定调节DBC1-SIRT1相互作用的机制非常重要。 DBC1-SIRT1相互作用的调节可能在不同代谢条件下的SIRT1功能（包括饮食诱导的脂肪变性）的调节中起关键作用。 DBC1和SIRT1之间的相互作用增加也可能为饮食诱导的肝脏脂肪变性动物模型报告的SIRT1活性的降低提供分子基础。因此，我们的中心假设是DBC1通过直接结合和抑制SIRT1在肝脏脂肪变性的发展中起着至关重要的作用，随后调节了SIRT1对肝脂肪生成的下游影响和通过AMPK进行2-氧化作用。为了检验这一假设，将解决以下具体目标：目标1。研究SIRT1在DBC1介导的肝脏脂肪变性调节中的作用。 AIM 2。表征DBC1在不同热量载荷中SIRT1活性调节中的作用，并确定调节DBC1-SIRT1相互作用的分子机制。 AIM 3。确定SIRT1下游的生化机制，通过该机制调节肝脏脂肪变性的发展：AMPK的作用。总的来说，这些研究将导致对DBC1作为SIRT1，肝脏脂肪代谢和肝脂肪变性的调节剂的生理作用的深入和非常新颖的理解。公共卫生相关性：非酒精性脂肪肝病（NAFLD）是全球主要的健康问题。正如美国美国肝病研究协会未来趋势会议的成员最近所说的那样，“总的来说，NAFLD患者的长期生存率降低了，肝病约占总体死亡率的10％，仅因恶性肿瘤和心血管死亡而超过。显然，NAFLD似乎在未来几年中变得更加普遍。这些令人震惊的数据和预测清楚地表明，必须进一步了解调节肝脏脂肪变性发展的分子机制。